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Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Renal+Physiol 2014 ; 307 (7): F800-5 Nephropedia Template TP
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Endogenous flow-induced superoxide stimulates Na/H exchange activity via PKC in thick ascending limbs #MMPMID25080525
Hong NJ; Garvin JL
Am J Physiol Renal Physiol 2014[Oct]; 307 (7): F800-5 PMID25080525show ga
Luminal flow stimulates Na reabsorption along the nephron and activates protein kinase C (PKC) which enhances endogenous superoxide (O2?) production by thick ascending limbs (TALs). Exogenously-added O2? augments TAL Na reabsorption, a process also dependent on PKC. Luminal Na/H exchange (NHE) mediates NaHCO3 reabsorption. However, whether flow-stimulated, endogenously-produced O2? enhances luminal NHE activity and the signaling pathway involved are unclear. We hypothesized that flow-induced production of endogenous O2? stimulates luminal NHE activity via PKC in TALs. Intracellular pH recovery was measured as an indicator of NHE activity in isolated, perfused rat TALs. Increasing luminal flow from 5 to 20 nl/min enhanced total NHE activity from 0.104 ± 0.031 to 0.167 ± 0.036 pH U/min, 81%. The O2? scavenger tempol decreased total NHE activity by 0.066 ± 0.011 pH U/min at 20 nl/min but had no significant effect at 5 nl/min. With the NHE inhibitor EIPA in the bath to block basolateral NHE, tempol reduced flow-enhanced luminal NHE activity by 0.029 ± 0.010 pH U/min, 30%. When experiments were repeated with staurosporine, a nonselective PKC inhibitor, tempol had no effect. Because PKC could mediate both induction of O2? by flow and the effect of O2? on luminal NHE activity, we used hypoxanthine/xanthine oxidase to elevate O2?. Hypoxanthine/xanthine oxidase increased luminal NHE activity by 0.099 ± 0.020 pH U/min, 137%. Staurosporine and the PKC?/?1-specific inhibitor Gö6976 blunted this effect. We conclude that flow-induced O2? stimulates luminal NHE activity in TALs via PKC?/?1. This accounts for part of flow-stimulated bicarbonate reabsorption by TALs.